Higher than standard dosing regimen are needed to achieve optimal antibiotic exposure in critically ill patients with augmented renal clearance receiving piperacillin-tazobactam administered by continuous infusion

Abstract Purpose To determine whether augmented renal clearance (ARC) impacts negatively on piperacillin-tazobactam unbound concentrations in critically ill patients receiving 16 g/2 g/day administered continuously. Material and methods Fifty nine critically ill patients without renal impairment underwent 24-h creatinine clearance (Cr CL ) measurement and therapeutic drug monitoring during the first three days of antimicrobial therapy by piperacillin-tazobactam. The main outcome was the rate of piperacillin underexposure, defined by at least one of three samples under 16 mg/L. Monte Carlo simulation was performed to predict the distribution of piperacillin concentrations for various Cr CL and minimal inhibitory concentration (MIC) values. Results The rate of piperacillin underexposure was 19%, significantly higher in ARC patients (0 vs. 31%, p  = .003). A threshold of Cr CL  ≥ 170 mL/min had a sensitivity and specificity of 1 (95%CI: 0.79–1) and 0.69 (95%CI: 0.61–0.76) to predict piperacillin underexposure. In ARC patients, a 20 g/2.5 g/24 h PTZ dosing regimen was associated with the highest probability to reach the 16 mg/L empirical target, without risk of excessive dosing. Conclusions When targeting a theoretical MIC at the upper limit of the susceptibility range, the desirable target (100%fT >16 ) may not be achieved in patients with Cr CL  ≥ 170 mL/min receiving PTZ 16 g/2 g/day administered continuously.